Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that takes a relapsing-remitting or a progressive course. Its counterpart in the peripheral nervous system (PNS) is chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). In addition, there are acute, monophasic disorders, such as the inflammatory demyelinating polyradiculoneuropathy termed Guillain-Barre syndrome (GBS) in the PNS, and acute disseminated encephalomyelitis (ADEM) in the CNS. Both MS and GBS are heterogeneous syndromes. In MS different exogenous assaults together with genetic factors can result in a disease course that finally fulfils the diagnostic criteria. In both diseases, axonal damage can add to a primarily demyelinating lesion and cause permanent neurological deficits. No single animal model exists that mimics all the features of human demyelinating diseases; rather, the available models reflect specific facets. Here, we focus on experimental autoimmune encephalomyelitis (EAE) and neuritis (EAN) as models in rat and mouse strains, and discuss their distinct histopathology and the roles played by different autoantigens.
Alzheimer's disease is characterized by the presence of neurofibrillary tangles and senile neuritic plaques in the brain. Tangles are aggregates of paired helical filaments composed of the microtubule-associated protein, tau, in a hyperphosphorylated state. Senile plaques have a core of amyloid beta-peptide derived by proteolysis of the amyloid precursor protein. A major hurdle in defining the pathogenic mechanisms in Alzheimer's disease is to understand how both amyloid p-peptide deposition and paired helical filament formation are biochemically linked. Recent genetic discoveries provide some clues, suggesting that components of two developmentally important signalling pathways, Notch and wingless, or the vertebrate homologue of wingless, Wnt, are involved.
Tumour cells have a lower extracellular pH (pH(e)) than normal cells; this is an intrinsic feature of the tumour phenotype, caused by alterations either in acid export from the tumour cells or in clearance of extracellular acid. Low pH(e) benefits tumour cells because it promotes invasiveness, whereas a high intracellular pH (pH(i)) gives them a competitive advantage over normal cells for growth. Molecular genetic approaches have revealed hypoxia-induced coordinated upregulation of glycolysis, a potentially important mechanism for establishing the metabolic phenotype of tumours. Understanding tumour acidity opens up new opportunities for therapy.
The uptake of nucleosides (for nucleobases) is essential for nucleic acid synthesis in many human cell types and in parasitic organisms that cannot synthesize nucleotides de novo. The transporters responsible are also the route of entry for many cytotoxic nucleoside analogues used in cancer and viral chemotherapy. Moreover, by regulating adenosine concentrations in the vicinity of its cell-surface receptors, nucleoside transporters profoundly affect neurotransmission, vascular tone and other processes. The recent molecular characterization of two families of human nucleoside transporters has provided new insights into the mechanisms of natural nucleotide and drug uptake and into future developments of improved therapies.
Excess scar formation secondary to traumatic or surgical injuries can have devastating consequences, ranging from body disfigurement to organ dysfunction, Hypertrophic scars and keloids are skin fibrotic conditions that can be caused by minor insults to skin, such as acne or ear piercing, or by severe injuries such as burns, Differences between keloids, hypertrophic scars and normal scars include distinct scar appearance, histologic morphology and cellular function in response to growth factors. Recent advances in our understanding of the wound healing process reveal possible causes for hypertrophic scars and keloids, This information might assist in the development of efficacious treatment for hypertrophic scar and keloid formation.
In 1996, we are half-way through the Decade of the Brain, yet we still have few effective treatments for major disorders of the central nervous system. These include affective disorders, epilepsy, neurodegenerative disorders, brain tumours, infections and HIV encephalopathy; sufferers far outnumber the morbidity of cancer or heart disease. Increased understanding of the pharmacology of the brain and its blood supply, and methods for rational drug design, are leading to potential new drug therapies based on highly specific actions on particular target sites, such as neurotransmitter receptors and uptake systems. These methods are capable of reducing the side effects that are common with more general treatments. However, all these treatments and potential treatments meet a formidable obstacle the blood-brain barrier. In this article, we review the properties of this barrier that complicate drug delivery to the brain, and some of the most hopeful strategies for overcoming or bypassing the barrier in humans.
Hematopoietic stem cells (HSCs) are the rare cells from which all hematopoietic cells are derived. The absence of HSCs is not compatible with life because many essential cells, such as myeloid and erythroid cells, are short lived. The hematopoietic system is the first essential organ system that fails following cytotoxic treatments. It is the vulnerability of HSCs that prevents regeneration following treatment and thus long-term survival. Because HSCs have the capacity to regenerate a functional hematopoietic system, the manipulation of these cells in vitro holds many promises for gene-therapeutic and other applications; however, these are severely curtailed by current difficulties in maintaining and expanding HSCs in culture. This review focuses on recent approaches towards understanding how the HSC compartment is regulated in vivo and discusses how this knowledge might be applied to manipulating HSC numbers.
We have become accustomed to the idea that the major disorders of adult life, including coronary heart disease, stroke and diabetes, arise through an interaction between factors in our lifestyle, such as a high-fat diet, obesity and smoking, and a genetically determined susceptibility. Recent research, however, suggests that growth in utero may also play an important role.
Specific vaccines for the immunotherapy of human neoplasms require specific human tumor antigens, While efforts to identify such antigens by the analysis of the T-cell repertoire have yielded few antigens, the application of SEREX, the serological identification of antigens by recombinant expression cloning, has brought a cornucopia of new antigens, Several specific antigens have been identified in each tumor tested, suggesting that many human tumors elicit multiple immune responses in the autologous host, The frequency of human tumor antigens, which can be readily defined at the molecular level, facilitates the identification of T-cell-dependent antigens and provides a basis for peptide and gene-therapeutic vaccine strategies.
The matrix metalloproteinases (MMPs) are a unique family of metalloenzymes, which, once activated, can destroy all the components of cartilage, MMPs are found in resorbing cartilage, bone, rheumatoid and osteoarthritic synovial fluid, and adjacent soft tissues. The active enzymes are all inhibited by tissue inhibitors of metalloproteinases (TIMPs), The relative amounts of active MMPs and TIMPs are important in determining whether cartilage is broken down in joint diseases, Conventional treatments for arthritis do little to affect the underlying joint destruction, but new drugs are now available that can specifically block active MMPs, These potent inhibitors prevent the destruction of cartilage both in vitro and in animal models of arthritis, Future trials in patients will test their effectiveness in the prevention of cartilage destruction.
Human serum paraoxonase (PON1) is an esterase that is bound to high-density lipoproteins (HDLs). It can hydrolyze organophosphates and its activity is inversely related to atherosclerosis. Some studies also suggest that a relationship exists between polymorphisms of the gene that encodes paraoxonase and coronary heart disease (CHD), whereas other studies, in different populations, have not found such an association. One mechanism by which certain PON1 allozymes might protect against atherosclerosis is by inhibition of the oxidation of HDL and low-density lipoprotein (LDL). Experimental studies suggest that this protection is associated with the ability of PON1 to hydrolyze specific lipid peroxides in oxidized lipoproteins. interventions that preserve or enhance PON1 activity, as well as manipulations of Pont polymorphisms, might help delay the onset of CHD.
Transforming growth factor-beta (TGF-beta) and related cytokines control the development and homeostasis of many tissues by regulating the expression of genes that determine cell phenotype, Recent progress has elucidated the way in which members of the TGF-beta family initiate their signal through transmembrane receptors and transmit it to target genes via the Smad family of signal-transducing proteins. This review describes TGF-beta signaling pathways as currently understood and mutations of the genes that encode Smads that disrupt the function of these proteins and cause various forms of cancer.
Compelling evidence indicates that HLA-B27 is directly involved in the etiopathogenesis of the spondyloarthropathies (SpAs). Several hypotheses based on its native antigenic structure, the peptides it presents and mimicry with bacterial epitopes, have been proposed. However, these potential mechanisms remain largely unsupported by human studies and transgenic animal models. Recent work demonstrating that HLA-B27 misfolds offers a novel alternative hypothesis. Here, we review this new information on the folding and assembly of HLA-B27, and discuss consequences of misfolding that could be relevant to the pathogenesis of SpAs.
Sonic hedgehog (Shh) is a morphogen that is crucial for normal development of a variety of organ systems, including the brain and spinal cord, the eye, craniofacial structures, and the limbs, Mutations in the human SHH gene and genes that encode its downstream Intracellular signaling pathway cause several clinical disorders, These include holoprosencephaly (HPE, the most common anomaly of the developing forebrain), nevoid basal cell carcinoma syndrome, sporadic tumors, including basal cell carcinomas, and three distinct congenital disorders: Greig syndrome Pallister-Hall syndrome, and isolated postaxial polydactyly, These conditions caused by abnormalities in the SHH pathway demonstrate the crucial role of SHH in complex developmental processes, and molecular analyses of these disorders provide insight into the normal function of the SHH pathway in human development.
Boron neutron capture therapy (BNCT) is currently undergoing clinical trials in the USA, Japan and The Netherlands with patients afflicted with deadly brain cancer (glioblastoma multiforme) or melanoma, This therapy relies on a binary process in which the capture of a slow neutron by a B-10 nucleus leads to an energetic nuclear fission reaction, with the formation of Li-7(3+) and He-4(2+) and accompanied by about 2.4 MeV of energy. The fleeting Li-7(3+) and He-4(2+) travel a distance of only about the diameter of one cell, and they are deadly to any cell in which they have been produced. Research in progress is concerned with the development of advanced boron agents and neutron sources, other than nuclear reactors, for the treatment of a variety of cancer types using novel B-10 delivery methods. Non-malignant diseases such as rheumatoid arthritis offer additional opportunities for BNCT, The entire BNCT area awaits commercialization.
Nitric oxide (NO) is a unique informational substance first identified as the endothelium-derived relaxing factor. It is generated by NO synthases and plays a prominent role in controlling a variety of organ functions in the cardiovascular, immune, reproductive and nervous systems. Inducible nitric oxide synthase (iNOS) is not normally present in the brain in youth but it can be detected in the brain after inflammatory, infectious or ischemic damage, as well as in the normal, aging brain. Brain INOS seems to contribute to the pathophysiology of many diseases that involve the central nervous system, but the role of iNOS appears to go beyond tissue damage. Brain iNOS might be required for adequate repair following injury or damage. The effects of brain iNOS on the balance between damage and repair make this enzyme a promising therapeutic target in human disease.
Human atherosclerosis has many characteristics of an inflammatory disorder. Recent data suggest that mast cells might be important in the pathogenesis of atherosclerotic disease. By secretion of pro-inflammatory cytokines, mast cells can assist in the recruitment of monocytes and lymphocytes into vascular tissue, thereby propagating the inflammatory response. Mast cell enzymes might activate pro-metalloproteinases, thereby destabilizing atheromatous plagues. Mast cells can facilitate foam cell formation by promoting cholesterol accumulation. However, mast cell tryptase could slow thrombus formation at sites of plaque rupture by interfering with coagulation. Therefore, mast cells can modulate coronary artery disease by both facilitatory and inhibitory pathways.
Human atopic dermatitis (AD) is a chronic pruritic (itchy) skin disease that affects 10-15% of the population of the Western world. The disease is seen mostly in children, with onset in approximately 85% of patients before the age of five years. The lesions are located in the flexural areas, such as the crooks of the elbows and knees, and on the wrist, the neck and the face. The lesions exhibit characteristics such as dry skin, thickening and, because of the pruritic nature of the disease, scratch marks. The lesions are infiltrated with CD4 super(+) T cells, eosinophils, mast cells and macrophages; numbers of dermal dendritic cells and epidermal Langerhans' cells are also increased at these sites. In addition, serum IgE levels are increased in most, but not all, AD patients.
The environment of the brain is controlled by a sophisticated endothelial barrier that prevents the free entry of solutes from the blood, It is commonly assumed that this brood-brain barrier (BBB) also prevents the entry of leukocytes into the central nervous system. However, recent evidence in animal models shows that this is not the case, and leukocytes can cross an intact BBB during health and disease, Indeed, in many neurological diseases, including Alzheimer's disease, prion diseases and AIDS-related dementia, leukocytes enter the brain parenchyma without concomitant BBB breakdown, Current research is concentrating on factors that control the integrity of the BBB and the mechanisms that leukocytes use to enter the brain.
Acute respiratory distress syndrome (ARDS) is a life-threatening lung injury that is characterized by arterial hypoxemia and noncardiogenic pulmonary oedema. One feature of ARDS is an alteration of pulmonary surfactant that increases surface tension at the air-liquid interface and results in alveolar collapse and the impairment of gas exchange. Type-II secretory phospholipase A(2) (sPLA(2)-II) plays a major role in the hydrolysis of surfactant phospholipids and its expression is inhibited by surfactant. Here, we discuss the evidence that in pathological situations, such as ARDS, in which surfactant is altered, sPLA2-II production is exacerbated, leading to further surfactant alteration and the establishment of a vicious cycle.